POS1342 DEPLETION OF KLRG1+ T CELLS IN A FIRST-IN-HUMAN CLINICAL TRIAL OF ABC008 IN INCLUSION BODY MYOSITIS (IBM)
Authors: N. Goel, M. Needham, D. Soler-Ferran, M. M. Cotreau, J. Escobar, S. Greenberg
Journal: Annals of the Rheumatic Diseases (2022)

Background Inclusion body myositis (IBM), a relentlessly progressive autoimmune skeletal muscle disease, has no effective available pharmacological therapy. A prominent feature of IBM on microscopy is highly differentiated effector CD8+ cytotoxic T (Tc) cells invading non-necrotic myofibers [1]. These Tc cells, known to be relatively resistant to apoptosis, express markers including killer cell lectin-like receptor G1 (KLRG1) [2]. ABC008, a first-in-class humanized, afucosylated monoclonal antibody (mAb) specific for KLRG1, selectively depletes these highly differentiated Tc cells while sparing other blood cell populations, e.g., naïve, central memory, and regulatory T cells and B cells. ABC008 has been designed to treat diseases mediated by these Tc cells, including IBM and T-cell large granular lymphocytic leukemia (T-LGLL). IBM and rheumatoid arthritis overlap clinically with T-LGLL and share similar expansions of large granular lymphocytes (LGLs), which also express KLRG1. We report here our preliminary data from our ongoing trial of ABC008 in IBM ( NCT04659031 ). Objectives Evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of ABC008 administered subcutaneously (SC) in adults with IBM. Methods In this first-in-human, open-label, single ascending dose trial with 3 + 3 design evaluating ABC008 SC, eligible participants must have clinicopathologically defined, clinically defined, or probable IBM according to the European Neuromuscular Centre 2011 research diagnostic criteria [3] and an IBM Functional Rating Scale (IBMFRS) score ≤38. Four dose cohorts are planned: ABC008 0.1, 0.5, 2.0, and 5.0 mg/kg. PD, PK, safety, and disease severity assessments are performed pre-dose (Day 0) and during the 6-month follow-up period. Results Five of the 6 (83.3%) participants were male with baseline mean age = 65.7 years, mean IBM disease duration = 6.8 years, and mean IBMFRS score = 27.5 (Table 1). Each received a single dose of ABC008 SC: Cohorts 1 (C1) and 2 (C2) received 0.1 and 0.5 mg/kg and have completed 168 and 56 days of follow-up, respectively. Table 1. Baseline Demographics Baseline Characteristics ABC008 SC Treatment Groups Cohort 10.1 mg/kg SC (n=3) Cohort 20.5 mg/kg SC (n=3) ABC008 Overall (N=6) Age (years), mean ± SD 64.0 ± 11.36 67.3 ± 6.66 65.7 ± 8.52 Male sex, n (%) 3 (100) 2 (66.7) 5 (83.3) Caucasian 3 (100) 3 (100) 6 (100) Body Mass Index (kg/m 2 ) 28.5 ± 3.58 28.3 ± 4.25 28.4 ± 3.52 Disease Duration (years), mean ± SD 9.7 ± 5.97 3.9 ± 4.48 6.8 ± 5.70 IBMFRS score, mean ± SD 30.0 ± 4.08 25.0 ± 6.16 27.5 ± 5.80 Abbreviations: IBMFRS, Inclusion Body Myositis Functional Rating Scale; n or N, number; SC, subcutaneous; SD, standard deviation. Maximum depletion of CD8+KLRG1+ cells for C1 and C2 ranged from 46-96% and 98-99%, respectively (Figure 1A), with depletion evident by the next assessment on Day 1. Recovery in C1 began at Day 84 with Day 168 depletion at 29-71%. Other hematologic parameters generally were stable (e.g., T regulatory and B cells). CD8+CD57+ LGLs, mostly KLRG1+, were also depleted (Figure 1B). Preliminary PK showed that ABC008 SC displays a long absorption phase and slow clearance properties typical of mAb therapies. No severe adverse events (AEs) or discontinuations due to AEs have been reported. One unrelated serious AE of fall with muscle tear in a C1 participant with a prior history of falls occurred. Figure 1. Key pharmacodynamic parameters in Study ABC008-IBM-101. Baseline and change (A) of KLRG1+CD8+ T cells and (B) CD8+CD57+ large granular lymphocytes (LGLs). C1 and C2 are Cohorts 1 and 2; P1, P2, and P3 are Participants 1, 2, and 3. Conclusion In study participants with IBM, single SC doses of 0.1 and 0.5 mg/kg of ABC008 resulted in the depletion of CD8+KLRG1+ cells and CD8+CD57+ LGLs with clear evidence of a dose response for KLRG1+ T cell depletion and no apparent safety signals. Based on these results, a study evaluating ABC008 for the treatment of T-LGLL is planned. References [1]Engel AG, et al. Ann Neurol. 1984;16:209-15. [2]Greenberg SA, et al. Brain. 2016;139:1348-60. [3]Rose MR, et al. Neuromuscul Disord. 2013;23:1044-55. Disclosure of Interests Niti Goel Shareholder of: UCB, Abcuro, Inc, Employee of: Abcuro, Inc, Merrilee Needham Consultant of: Abcuro, Inc, Grant/research support from: Abcuro, Inc, Dulce Soler-Ferran Shareholder of: Abcuro, Inc, Employee of: Abcuro, Inc, Monette M. Cotreau Consultant of: Abcuro, Inc, Jorge Escobar Shareholder of: Abcuro, Employee of: Abcuro, Steven Greenberg Shareholder of: Abcuro, Inc, Consultant of: Abcuro, Inc